This project will characterize genetic loci involved in fetal-onset hydrocephalus in two rat models, through a combination of genome scanning and classic linkage analysis. The study will use two unrelated rat strains, H-Tx and LEW/Jms. Each develops hydrocephalus at 18 days of gestation (a stage equivalent to 20 weeks gestation in humans). H-Tx has a complex pattern of inheritance, whereas LEW/Jms has a simple autosomal recessive mode of inheritance. Preliminary data have identified hydrocephalus-linked loci on chromosomes 11 and 17. Fine mapping will be used to further narrow these regions of interest, and other putative regions to be identified by all-genome scanning. A congenic breeding strategy will be used to further narrow critical regions and assess the relative contribution of the loci to the phenotype. Reducing the genomic intervals will ultimately lead to positional cloning of novel genes or identification of previously mapped candidate genes.